COVID-19 Treatments & Pipeline (Continued)

SARS-CoV-2 and COVID-19 have dominated the news and changed the world as we know. Information and data abounds and impacts our daily life. While we all grip with the shock that the coronavirus has had since the World Health Organization (WHO) declared a global health emergency on January 30, 20201, this continuing series is intended to provide a brief summary and update of the available clinical information and pipeline for COVID-19 treatments and to assist with the management and impact of this outbreak on your benefit and members.

As outlined in our March 2020 update, many treatments are being used or studied around the globe for activity in COVID-19. These therapies are not yet FDA approved for treatment of COVID-19, but some have gathered large media followings, including hydroxychloroquine and chloroquine. These agents are in shortage due to a surge in demand because of the coronavirus pandemic. The FDA is working with companies making generic versions of the drugs to ramp up production and assist with continuing patients on their existing therapies as well as providing additional supplies for COVID-19 treatements.13 The FDA has a new program, the Coronavirus Treatment Acceleration Program (CTAP), intended to expedite the development of potentially safe and effective life-saving treatments. This program is designed to assist the FDA is triaging requests to develop new drug and biologic therapies.10

Many trials, both clinical and non-clinical, are underway to evaluate safe and efficacious treatment options. The following are summaries of additional trials or case reports:

Influenza Antivirals (Oseltamivir [Tamiflu], Favipiravir [Avigan]3, 8, 16

Oseltamivir, a neuraminidase inhibitor, is an antiviral currently active and used in the treatment of influenza viruses. It is widely reported that oseltamivir has been used for confirmed or suspected COVID-19 cases in hospitals in China and other high impact areas. Unfortunately, there has been little published evidence to date that oseltamivir is effective in the treatment of COVID-19. There continues to be oseltamivir clinical trials for COVID-19; however, they are just starting to recruit. Another influenza antiviral, favipiravir, available as Avigan internationally but not in the US, was reported to be tested in clinical trials with COVID-19 patients in China. It was reported that the favipiravir treatment group showed a shorter viral clearance time than the control group receiving Kaletra® (lopinavir/ ritonavir). The antiviral activity of favipiravir is slightly different from oseltamivir, targeting the viral RNA polymerase, making it a potential treatment for COVID-19, provided if the SARS-CoV-2 RNA polymerase is similar enough to the influenza polymerase. The study used two 1,600mg doses of favipiravir on the first day and two doses of 600mg for the following 13 days, in addition to interferon- alpha aerosol inhalation, led to faster viral clearance than the Kaletra group, with a median of 4 days versus 11 days, as well as improvement in seen in chest imaging.

1055 Westlakes Dr. Suite 175 Berwyn, PA 19312 | AscellaHealth.com | 877-389- 9040 COVID-19 Treatments & Pipeline (Continued)

Convalescent Plasma6, 7, 12

Another investigational treatment involves the use of convalescent plasma collected from patients who have recovered from COVID-19. It is thought that this convalescent plasma contains antibodies to SARS-CoV-2 that may transfer this activity to current infected patients. An early case report from China of 5 critically ill patients with COVID-19 and acute respiratory distress syndrome (ARDS), indicated that administration of convalescent plasma containing neutralizing antibody demonstrated an improvement in clinical status. All 5 patients (age range, 36-65 years; 2 women) were receiving mechanical ventilation and had received antiviral agents and IV steroids. On March 24th, the FDA has allowed physicians to use plasma from recovered patients to treat those with serious or immediately life-threatening COVID-19 infections under their emergency approval system. Results of these cases are not yet published.

Monoclonal Antibiodies2, 5

Similar to the convalescent plasma, researchers in China have identified neutralizing monoclonal antibodies from recovered COVID-19 patients that have shown therapeutic potential. A collaborative effort between the hospital and industry are identifying lead candidates and to aim to begin human trials by fall of 2020. Additionally, mavrilimumab, an investigational human monoclonal antibody targeting granulocyte macrophage colony stimulating factor alpha (GM-CSFRα), from Kiniksa Pharmaceuticals, has been reported to show promise from a small case report in Italy. It is postulated that by blocking GM-CSF signaling, mavrilimumab works upstream of interleukin-6 and potentially addresses the underlying pathophysiology of the hyperinflammation which may be responsible for the severe pneumonia of COVID-19. Six patients were treated and all patients showed an early resolution of fever and improvement in oxygenation within 1-3 days, without progression to mechanical ventilation.

Immunoglobulin (IVIg) & Immunotherapy9, 14

A case report from China indicated that three patients with severe COVID-19 were treated with high- dose IVIg at an early stage of clinical deterioration. IVIg is speculated to block the progression of the disease cascade and avoid significant complications associated with COVID-19. All three patients demonstrated a positive clinical response.

Additionally, development has begun on inhaled forms of mRNA-encoded, neutralizing anti-SARS- CoV-2 antibodies recovered from COVID-19 patients. The inhaled form is targeted to provide immunotherapy to produce therapeutic antibodies directly in the lung of affected patients.

1055 Westlakes Dr. Suite 175 Berwyn, PA 19312 | AscellaHealth.com | 877-389- 9040 COVID-19 Treatments & Pipeline (Continued)

Interferon Beta 1a11

An initial trial in the UK has been initiated with an inhaled formulation of interferon-beta-1a in COVID-19 patients. It is thought that the addition of exogenous interferon-beta before or during an active viral infection of lung cells would either prevent or diminish cell damage and viral replication, leading to enhanced recovery. The Phase II trial is being sponsored by Synairgen using a proprietary formulation of nebulized interferon. The initial phase of the trial at six international sites is targeted to enroll 100 COVID-19 patients and began in March 2020.

Casein Kinase 2 Inhibitors4

Silmitasertib, an orphan drug from Senhwa Biosciences, is a first-in-class, oral drug that targets (CK2). This is a protein involved in the DNA repair mechanism of cancer cells. Initial clinical studies have shown that silmitasertib, in combination with other agents, improved the efficacy of treatments. It is speculated that by inhibiting CK2, the cellular environment of COVID-19 could potentially shift into a more antiviral state resulting in the inhibition of COVID-19 proliferation and improve patient outcomes. Clinical trials have not yet been initiated.

Vaccine1, 15

An initial SARS-CoV-2 vaccine trial was initiated in March by the NIAID. Additionally, Johnson & Johnson announced that they intend to initiate human clinical studies of their lead vaccine candidate, with two additional back-ups, by September 2020. They anticipate through an accelerated timeline, the first batches of a COVID-19 vaccine could be available for emergency use authorization in early 2021. No details on the lead or back-ups candidates or the clinical trial are yet available.

Information will continue to evolve as more clinical data, including publicized case reports, and initial results of clinical drug trials become available and is evaluated and vetted by the medical community. Some of these agents show initial promise, but controlled clinical information is needed to evaluate their potential impact on COVID-19. AscellaHealth is committed to assisting our clients in providing the optimal care to your members and their communities. If you have any questions, please reach out to your AscellaHealth contact.

1055 Westlakes Dr. Suite 175 Berwyn, PA 19312 | AscellaHealth.com | 877-389- 9040 COVID-19 Treatments & Pipeline (Continued)

References

1. https://www.jnj.com/johnson-johnson-announces-a-lead-vaccine-candidate-for-covid-19-landmark-new- partnership-with-u-s-department-of-health-human-services-and-commitment-to-supply-one-billion- vaccines-worldwide-for-emergency-pandemic-use; Accessed March 31, 2020 2. https://www.biorxiv.org/content/10.1101/2020.03.21.990770v2; Accessed March 31, 2020 3. https://www.clinicaltrialsarena.com/comment/influenza-favipiravir-covid-19/; Accessed April 2, 2020 4. https://www.biospace.com/article/releases/senhwa-biosciences-silmitasertib-named-as-potential-covid- 19-therapy/; Accessed March 31, 2020 5. https://investors.kiniksa.com/news-releases/news-release-details/kiniksa-announces-early-evidence- treatment-response-mavrilimumab; Accessed March 31, 2020 6. https://jamanetwork.com/journals/jama/fullarticle/2763983; Accessed March 31, 2020 7. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide- process-cber/investigational-covid-19-convalescent-plasma-emergency-inds; Accessed March 31, 2020 8. IPD Analytics, Infectious Disease: Coronavirus; Accessed April 1, 2020 9. Cao, W, et al; High Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients with Coronavirus Disease 2019; Infectious Diseases Society of America, Open Forum Brief Report, Accepted March 19. 2020; publication pending; Accessed April 1, 2020 10. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues- accelerate-development-novel-therapies-covid-19; Accessed April 1, 2020 11. https://www.synairgen.com/wp-content/uploads/2020/03/Commencement-of-dosing-in-COVID-19- trial-31-03-20.pdf; Accessed April 1, 2020 12. https://jamanetwork.com/journals/jama/fullarticle/2763983; Accessed April 2, 2020 13. https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm; Accessed April 2, 2020 14. https://www.neurimmune.com/news/neurimmune-and-ethris-sign-collaboration-agreement-to-rapidly- develop-inhaled-mrna-based-antibody-therapy-for-the-treatment-of-covid-19; Accessed April 2, 2020 15. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-investigational-vaccine-covid-19- begins; Accessed March 27, 2020 16. https://iris.paho.org/handle/10665.2/51949; Accessed April 2, 2020

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